Early studies focused on septic shock pathophysiology (Am J Physiol 1988; Chest 1990), the role of endotoxemia (J Clin Invest 1989; J Exp Med 1989; Chest 1991; N Engl J Med 1993; Infect Immun 1996), and the efficacy of various anti-endotoxin therapies (Antimicrob Agents Chemother 1989) including lipid A analogs (J Clin Invest 1987; Pharm Res 1990) and antibodies (JAMA 1993; J Infect Dis 1994). Nitric oxide (NO) was examined as an important mediator of septic shock (Crit Care Med 1993; JAMA 1996). Non-selective NO synthase inhibitors were found to be sometimes toxic and never beneficial (J Exp Med 1992; Crit Care Med 1998; Am J Respir Crit Care Med 1998). Increased NO production in normal volunteers challenged with endotoxin was blocked by ibuprofen, but blood pressure was unaffected, suggesting that other mechanisms compensated to maintain vasodilation (J Pharmacol Exp Ther 1999). Severity of illness (risk of death) influenced the therapeutic efficacy of anti-inflammatory agents in septic shock (Am J Respir Crit Care Med 2002). L-arginine without or with N-acetylcysteine in a canine model of septic shock was found to be harmful (Crit Care Med 2006). L-arginine had been a component of immunonutrition formulas marketed for use in critically ill patients. A canine septic shock model was redeveloped to balance animal welfare and scientific relevance. Both specific and supportive titrated therapies routinely used in patients were fully integrated into the model (Am J Physiol Heart Circ Physiol 2007). Whether risk of death altered the effects of hydrocortisone was investigated in a mouse model of E. coli pneumonia (Intensive Care Med 2008). Intra-aortic balloon counterpulsation was found to prolong survival in a hypodynamic canine model of Staphylococcal pneumonia-induced septic shock (Crit Care Med 2009). Low cardiac output is seen in 10 to 20 percent of adults and up to 50 percent of children with septic shock. The U.S. Critical Illness and Injury Trials Group (USCIITG; http://www.usciitg.org/) was founded to create a clinical research framework that can reduce the barriers to investigation (Crit Care Med 2009). A meta-analysis of bundled care for septic shock demonstrated consistent and significant improvements in survival that were only strongly associated with early and appropriate antibiotics and not other bundle components (Crit Care Med 2010). SB203580, a p38 inhibitor, improved cardiac function but worsened lung injury and survival during E. coli pneumonia in mice (J Trauma 2010). Fluids and vasopressors, standard approaches to septic shock were harmful in a rat model of anthrax lethal toxin (LeTx)-induced shock (Crit Care Med 2009). In sedated canines receiving mechanical ventilation, edema toxin increased mortality when added to equimolar lethal toxin challenges (J Infect Dis 2010). Heparin in a mouse model of E. coli pneumonia failed to improve lung injury or survival (Crit Care Med 2011). Corticosteroids that activate both mineralocorticoid (MR) and glucocorticoid receptors (GR) consistently reverse vasopressor-dependent hypotension in septic shock, but have variable effects on survival. In a canine model of S. aureus pneumonia-induced septic shock, MR and GR selective agonists were examined separately. Mineralocorticoid was only beneficial if given prophylactically, while glucocorticoid was most beneficial when given close to the onset of infection (Crit Care Med 2012). Stress dose corticosteroids were only beneficial in sepsis with a high risk for death (Intensive Care Med 2012). Tigecycline was found to be associated with increased mortality and non-cure. Effects were not isolated to type of infection or comparator antibiotic regimen, and the impact on survival remained significant when limited to trials of approved indications (Clin Infect Dis 2012). Staphylococcal enterotoxin including B (SEB) can trigger a lethal superantigen-mediated cytokine storm. These exotoxins contribute to the high mortality of S. aureus sepsis and are a potential bioweapon threat. Using an aerosolized-toxin mouse model, gene-expression changes across multiple organs implicated a host-wide IFN-response in SEB-induced death (PLoS One 2014). Hypothalamic-pituitary-adrenal (HPA) function was characterized serially over five days in 101 canines with severe Staphylococcus aureus pneumonia. HPA axis unresponsiveness and high aldosterone levels identified a septic shock subpopulation with poor outcomes that may have the greatest potential to benefit from new therapies (Am J Physiol Endocrinol Metab 2014). Infections caused by multidrug-resistant and extensively drug-resistant gram-negative organisms are an important emerging threat to critically ill patients worldwide. Intravenous colistin administration identified a severely ill population with a high probability of having culture-confirmed extensively drug-resistant bacteria. Colistin-cases at 40 academic medical centers nearly trebled over 7 years (Clin Infect Dis 2015). Meningoencephalitis was documented for the first time in a patient with Ebola virus disease at the NIH Clinical Center (Ann Intern Med 2016). The Surfactant, Positive Pressure, and Pulse Oximetry Randomized Trial (SUPPORT) consent forms suggested that the low oxygen saturation arm was a widely practiced subset of usual care. An analysis of usual care practices demonstrated that oxygen targets and other interventions in the trial differed substantially from routine management outside of the trial (PLoS One 2016). A survey of intensivists found that diagnosing sepsis is extremely subjective and variable, indicating the need for objective and standardized critieria (Critcal Care 2016). Toxoplasmosis encephalitis was complicated by immune-reconstitution inflammatory syndrome (IRIS), in an allogeneic stem cell transplant patient (Bone Marrow Transplant 2016). A clinical surveillance definition based on concurrent vasopressors, blood cultures, and antibiotics accurately identified septic shock hospitalizations and suggested that the incidence of septic shock has risen and mortality rates have fallen, but less dramatically than estimated using ICD-9 codes (Chest 2017). In a propensity-score matched cohort of patients from 130 US hospitals, adjunctive intravenous immunoglobulin (IVIG) was administered infrequently for necrotizing fasciitis with vasopressor-dependent shock and had no apparent impact on mortality or hospital LOS beyond that achieved with debridement and antibiotics (Clin Infect Dis 2017). Meta-analysis of available data in patients with cardiovascular disease demonstrated that a restrictive vs.liberal transfusion trigger was associated with an increased risk of death and acute coronary events (submitted). Using electronic clinical data from over 400 hospitals, we estimated 1.7 million adults nationwide with serious infections and concurrent organ dysfunction in 2014. Sepsis incidence was stable between 2009-2014; hospital mortality decreased but the combined outcome of death or discharge to hospice was stable (submitted). Difficult to Treat Resistance (DTR) was defined as the treatment-limiting burden of resistance to all high-efficacy, low-toxicity antibiotics (penicillins, cephalosporins, carbapenems, and quinolones). A multicenter repository of hospitalized patients was examined to determine the prevalence of DTR gram-negative bloodstream infections and its impact on mortality (submitted). Using inpatient encounters across 156 hospitals from 2000-2014 in the Cerner Healthfacts database prevalence of discordant antibiotic therapy displayed extensive taxon-level variability and was associated with patient and institutional factors. Discordance detrimentally impacted survival in gram negative and S. aureus bloodstream infections (in preparation).